Currently available anti-depressant and anti-anxiety drugs target the bio-synthetic, degradative and operative pathways of monoamine neurotransmitters such as norepinephrine, dompamine and, in particular, serotonin (5-hydroxy-tryptamine or 5-HT). Serotonin, first discovered in the late 1940's, plays a crucial role in modulating numerous functions in the body including mood, sleep, appetite and sexual activities. It functions both as a neurotransmitter within the central nervous system and also as a peripheral signal modulator. Consequently, alterations in serotonin availability and activity have been linked to depression, eating disorder (e.g. bulimia), obsessive compulsive disorders (OCD), drug addiction, attention deficit disorder (ADD), attention deficit hyperactive disorder (ADHD), premenstrual syndrome, anxiety disorders, aggression, sleep disorders, sexual dysfunction, gastrointestinal disorders (e.g. irritable bowel syndrome), mania, migrane, and bipolar disorder. Conventional anti-depressants typically regulate the signal transmission by either (1) preventing the degradation of serotonin by inhibiting monoamine oxygenase or (2) increasing neuronal transport of serotonin by inhibiting serotonin re-uptake by the presynaptic neurons. Despite over half a century of intensive study of serotonin pathways, however, the understanding of these pathways is incomplete, and there are no established biochemically-based diagnostics or biomarkers for serotonin pathway dysfunction.
5-HT (serotonin) receptors are heterogeneous and are found on the surface of a variety of cells. The 5-HT1B receptor is one of 14 serotonin receptor subtypes and is found abundantly throughout the central nervous system. The structure, distribution and apparent function of 5-HT1B receptors are very similar in rodents and humans. This receptor has been linked to a diverse range of physiologic functions and behaviors including mood, cognition, aggression, addiction, sleep and feeding. 5-HT1B receptors are found both on serotonin- and nonserotonin-containing neurons. 5-HT1B receptors are found predominantly on the pre-synaptic portion of the neuron, where they function as terminal autoreceptors involved in the regulation of serotonin release by neurons. When stimulated by binding to serotonin, they inhibit the release of additional serotonin by the neuron; when not stimulated, serotonin release is enhanced. Blocking of these 5-HT1B receptors thus tends to enhance serotonin levels. There is some evidence that 5-HT1B receptors are heteroreceptors, involved in controlling the release of other neurotransmitters, such as acetylcholine, glutamate, dopamine, norepinepherine and gamma-aminobutyric acid, as well as serotonin. Some 5-HT1B receptors are also found post-synaptically. The 5-HT4 receptor is found in the gastrointestinal system, where it is involved in gastrointestinal motility, as well as the central nervous system. Whereas 5-HT1B is generally associated with a decrease in cAMP, the 5-HT4 receptor is associated with increased cAMP activity. 5-HT4 receptors in the brain modulate neurotransmitter (acetylcholine, dopamine, serotonin and GABA) release and enhance synaptic transmission. They may also play a role in memory enhancement, by promoting release of non-amyloidogenic soluble amyloid precursor protein (sAPPalpha). As Alzheimer's disease is widely thought to be mediated by deposition of beta-amyloid plaque formation, enhancing 5-HT4 receptor function, thereby enhancing release of sAPPalpha, represents a potential approach to treatment or prophylaxis of Alzheimer's disease.
The protein p11 is a member of the S100 EF-hand protein family. p11 is also known as annexin-II light chain, lipocortin-II light chain, calpactin I light chain, 42C, or S-100 related protein, and these terms may be used interchangeably herein. R. Donato, Biochim. Biophys. Acta, 1450, 191 (1999). It is present in a variety of cells separately or as a heterotetramer. The heterotetramer is composed of two copies of p36, also known as armexin-II or calpactin-I heavy chain, and two copies of p11. Within the cell, the heterotetramer is localized at the cytoplasmic surface of the plasma membrane in the submembranous cytoskeleton, and it is suggested that the complex may play a role in membrane trafficking events such as exocytosis, endocytosis and cell-cell adhesion. p11 has been claimed to have a role in tumor cell invasion, tumor growth, and metastasis. US 2004/0142897A1. p11 has not previously been identified as being involved with 5-HT receptors or psychiatric disorders.